The overall objective is to better understand the interaction of structure and function in the design of the respiratory system in peripheral tissue (skeletal muscle and heart). The estimation of O2 diffusion, as well as substrate uptake, redistribution and output, in the muscle fibers depends on several morphometric parameters including capillarity, the model chosen to describe the diffusion of O2 and other metabolites, and the distances these substances need to travel between capillaries and mitochondria and/or myofibrils. Since Krogh's pioneering "plea for the study of quantitative anatomy" to model peripheral gas exchange, quantitative data essential to the analysis of diffusion pathways and their relation to maximal O2 uptake, tissue O2 demand, and the environmental O2 availability have been either lacking or controversial. We propose to correlate morphometric estimates of diffusion pathways (intercapillary distances, mitochondrial density and distribution within the muscle fibers) and capillary geometry in the same muscles. We will analyze animals 1) differing in O2 demand in normoxic conditions (terrestrial mammals of different size and performance; reptiles; birds), 2) exposed to acute and chronic hypoxia (mammals and birds given low 02 mixtures to breathe, and at high altitude), and 3) tolerant to extreme anoxia (diving marine mammals with different energy requirements; birds acclimated to higher altitude). Different skeletal muscles (mostly aerobic, glycolytic and mixed muscles), and the heart will be analyzed in each animal group. Our specific aims are 1) to determine how muscle capillary geometry (capillary to fiber ratio, sharing factor, capillary sinuosity and density of anastomoses) is related to O2 needs, 2) to test the hypothesis that the Hill model is more appropriate than the Krogh cylinder geometry to model O2 supply to contracting muscles, 3) to determine how capillary volume and geometry are related to to oxygen diffusion vs substrate delivery and lactate redistribution, 4) to determine structure-function relationships in the design of the respiratory system of muscles in the mammalian, reptile and bird models, and 5) to evaluate which adaptative changes can occur (or not) in the design of peripheral tissue in response to limited environmental O2. This will provide new insights in the understanding of structure-function correlations in tissue gas-exchange, and possibly help in the understanding of human response to hypoxemia.